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Clinical and Vaccine Immunology, September 2008, p. 1345-1355, Vol. 15, No. 9
1071-412X/08/$08.00+0     doi:10.1128/CVI.00172-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Comparative Testing of Six Antigen-Based Malaria Vaccine Candidates Directed Toward Merozoite-Stage Plasmodium falciparum{triangledown}

David E. Arnot,1,2* David R. Cavanagh,2,{dagger} Edmond J. Remarque,3,{dagger} Alison M. Creasey,2 Mercy P. K. Sowa,1 William D. Morgan,4 Anthony A. Holder,4 Shirley Longacre,5 and Alan W. Thomas3

Centre for Medical Parasitology, Institute for International Health, Immunology and Microbiology, University of Copenhagen, Øster Farimagsgade 5, bygning 22 & 23, Postboks 2099, 1014 Copenhagen K, Denmark,1 Institute of Immunology and Infection Research, Division of Biological Sciences, Ashworth Laboratories, University of Edinburgh, King's Buildings, West Mains Road, Edinburgh EH9 3JT, United Kingdom,2 Biomedical Primate Research Centre, Department of Parasitology, Lange Kleiweg 1339, 2288 GJ Rijswijk, The Netherlands,3 Division of Parasitology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom,4 Institut Pasteur, Rue du Dr. Roux, Paris, France5

Received 15 May 2008/ Accepted 29 May 2008

Immunogenicity testing of Plasmodium falciparum antigens being considered as malaria vaccine candidates was undertaken in rabbits. The antigens compared were recombinant baculovirus MSP-119 and five Pichia pastoris candidates, including two versions of MSP-119, AMA-1 (domains I and II), AMA-1+MSP-119, and fused AMA-1/MSP-119). Animals were immunized with equimolar amounts of each antigen, formulated in Montanide ISA720. The specificities and titers of antibodies were compared using immunofluorescence assays and enzyme-linked immunosorbent assay (ELISA). The antiparasite activity of immunoglobulin G (IgG) in in vitro cultures was determined by growth inhibition assay, flow cytometry, lactate dehydrogenase assay, and microscopy. Baculovirus MSP-119 immunizations produced the highest parasite-specific antibody titers in immunofluorescence assays. In ELISAs, baculovirus-produced MSP-119 induced more antibodies than any other single MSP-119 immunogen and three times more MSP-119 specific antibodies than the AMA-1/MSP-119 fusion. Antibodies induced by baculovirus MSP-119 gave the highest levels of growth inhibition in HB3 and 3D7 parasite cultures, followed by AMA-1+MSP-119 and the AMA-1/MSP-119 fusion. With the FCR3 isolate (homologous to the AMA-1 construct), antibodies to the three AMA-1-containing candidates gave the highest levels of growth inhibition at high IgG concentrations, but antibodies to baculovirus MSP-119 inhibited as well or better at lower IgG concentrations. The two P. pastoris-produced MSP-119-induced IgGs conferred the lowest growth inhibition. Comparative analysis of immunogenicity of vaccine antigens can be used to prioritize candidates before moving to expensive GMP production and clinical testing. The assays used have given discriminating readouts but it is not known whether any of them accurately reflect clinical protection.

* Corresponding author. Mailing address: Institute for International Health, Immunology and Microbiology, University of Copenhagen, Øester Farimagsgade 5, Bygning 22 & 23, Postboks 2099, 1014 Copenhagen K, Denmark. Phone: 45 35 32 78 65. Fax: 45 35 32 78 51. E-mail: d.e.arnot{at}cmp.dk

{triangledown} Published ahead of print on 11 June 2008.

{dagger} D.R.C. and E.J.R. contributed equally to this study.

Clinical and Vaccine Immunology, September 2008, p. 1345-1355, Vol. 15, No. 9
1071-412X/08/$08.00+0     doi:10.1128/CVI.00172-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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